...A team of bioengineers from Rice University is bringing a promising ne...Tissue-engineering researcher Jane Grande-Allen the lead investigator... It's ironic because they turned out to be one of the most difficult a...Grande-Allen said it's been difficult for engineers to find synthetic ...

A team of bioengineers from Rice University is bringing a promising new strategy for growing replacement heart valves closer to reality, thanks to a four-year, $1.2 million grant from the National Institutes of Health. The team hopes to use gel-like materials to generate three-dimensional patterns called scaffolds that can simultaneously mimic the complex structural and physical properties of heart-valve tissues and guide the behavior of tissue-forming cells.

Tissue-engineering researcher Jane Grande-Allen, the lead investigator on the grant, said researchers once believed that replacement heart valves would be one of the easiest and first tissues that could be grown in the laboratory. At just a millimeter thick, the rugged flaps of tissue in heart valves seemed simple enough when researchers first started trying to engineer them in the mid-1990s.

"It's ironic because they turned out to be one of the most difficult and complex tissues of all," said Grande-Allen, associate professor in bioengineering at Rice.

Grande-Allen said it's been difficult for engineers to find synthetic materials that truly mimic the complex structure and mechanical properties of heart-valve "leaflets," the tough yet flexible flaps of tissue that form a tight seal to prevent blood from flowing backward each time the heart pumps. Having materials that can both mimic the leaflets' microscopic structure and act as a pattern for tissue-forming stem cells has been a missing link in growing replacement heart valves.

Each aortic or pulmonary heart valve contains a trio of leaflets. Prior to each heartbeat, the leaflets open, like the petals of a blooming flower, allowing blood to flow into one of the heart's chambers. Then the leaflets fold back, interlocking with one another to form a tight seal that prevents blood from flowing backward. In cases of heart-valve disease, the valves don't seal properly, and the heart must pump much harder to deliver sufficient amounts of blood.

More than 90,000 Americans are hospitalized each year for heart-valve disease, and with too few human valves available for transplant, the most common surgical options are mechanical valves, which are noisy and require patients to stay on anticlotting medications for life, and artificial valves made of biological material, usually from pigs, which wear out after about 15 years.

Ideally, tissue engineers would like to grow living valves that use a patient's own cells to eliminate the risk of tissue rejection. But engineers have struggled to find nontoxic, biodegradable materials that can act as a scaffold to guide the cells' behavior. The ideal scaffold will have the same mechanical properties of a valve so that it can be surgically implanted and function as a valve, even as cells grow new tissue to replace it.

Grande-Allen said the fact that valve leaflets have three distinct layers has presented serious complications to creating scaffolds. Leaflets have a soft, malleable layer sandwiched between denser outer layers. The soft layer adds flexibility and sits between outer layers that have subtly different properties. The upshot is that to truly mimic the valves, engineers must design a multilayered scaffold.

"That hasn't been done before, but we have a real shot at success with some of the new methods that have been developed here at Rice in recent months that will allow us to cross-link, layer and reinforce hydrogel scaffolds to have spatially varying mechanical behavior," Grande-Allen said.

Grande-Allen and co-principal investigator Jennifer West, department chair and the Isabel C. Cameron Professor of Bioengineering at Rice, will work with several graduate students to create a multilayered, patterned scaffold with new techniques initially developed by West's team and then further refined in collaboration with Grande-Allen's laboratory. The key technique is one that allows researchers to selectively reinforce soft, nontoxic polymer scaffolds so that they'll mimic the various leaflet layers and won't peel apart.

"We're taking a very pragmatic approach," Grande-Allen said. "We have the tools to make a lot of headway in designing appropriate patterns, but we want to make certain the class of materials that we're planning to work with will ultimately be translatable to create functional valves."

Grande-Allen's and West's laboratories are located in Rice's BioScience Research Collaborative (BRC), an innovative space where scientists and educators from Rice and other Texas Medical Center institutions work together to conduct research that benefits human medicine and health.

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